Breast cancer is one of the most common causes of cancer deaths in women. In the United States, it accounts for 30% of all malignancies that affect women, excluding non-melanoma skin cancer. About one-third of newly diagnosed patients will eventually recur and/or develop metastatic disease.
Approximately 25% of patients with breast cancer have tumors that over-express HER2. Data from large, international trials of adjuvant regimens for primary breast cancer in the pre-trastuzumab era have shown a significant survival benefit with anthracycline-containing regimens compared to non-anthracycline regimens in breast cancer patients who had strongly HER2+ tumors. An anthracycline based regimen is recommended in most cases for women with node positive breast cancer as well as high risk pre-menopausal women with node negative breast cancer.
Doxorubicin is one of the most active and versatile anticancer agents. It has an exceptionally broad spectrum of activity and plays a leading role in the curative and palliative therapy of a diverse group of malignancies, most notably breast cancer, lymphoma, soft tissue sarcoma, various pediatric malignancies, multiple myeloma, and advanced bladder cancer. However, doxorubicin is associated with serious and sometimes life threatening side effects. In particular, doxorubicin's use is limited by the potential for patients to suffer irreversible cardiotoxicity. The incidence of clinically significant cardiomyopathy or congestive heart failure rises with increasing lifetime cumulative doses of doxorubicin. For this reason, most clinicians limit a patient's lifetime cumulative dose of doxorubicin to 450 mg/m2 or less. Sub-clinical and occasionally overt cardiotoxicity may also occur at lower cumulative doses of doxorubicin, especially when the drug is given as part of a combination regimen that includes drugs such as cyclophosphamide or paclitaxel, as well as newer biologic therapies, including trastuzumab.
Clinically relevant cardiotoxicity has been a particular issue in combination regimens of doxorubicin and the taxanes, especially paclitaxel, and to a lesser extent docetaxel and albumin-bound paclitaxel (Abraxan®). Three-fold greater cardiac toxicity was seen in women receiving the combination of trastuzumab and an anthracycline (either doxorubicin or epirubicin) and cyclophosphamide (AC), compared with the rates of cardiotoxicity that would have been expected with AC or trastuzumab alone. The same clinical trials also suggested that despite the high rates of cardiac toxicity, the combination of anthracyclines with trastuzumab (and cyclophosphamide) might actually be more efficacious in the metastasized breast cancer (MBC) setting compared to the FDA-approved paclitaxel/trastuzumab regimen. In particular, improved efficacy with AC and trastuzumab compared with paclitaxel/trastuzumab was notable with respect to time to disease progression and overall survival.
Doxorubicin and trastuzumab are known to be cardiotoxic, and their concomitant combined use presents a significant risk of cardiotoxicity. The risk of cardiotoxicity from treatment with doxorubicin and trastuzumab is believed to be enhanced for patients who have received prior treatment with an anthracycline.
Patients with HER2+ breast cancer have been treated with nonpegylated liposomal doxorubicin in combination with paclitaxel and trastuzumab in Phase I and Phase II clinical trials. Patients who received prior administration of any anthracycline were excluded from these earlier trials, due to the anticipated cardiotoxicity from accumulated anthracycline dosing.
Accordingly, it is an object of the present invention to provide a method for treating metastatic breast cancer in an individual who has previously been administered an anthracycline.